Extreme sensitivity to acenocoumarol therapy in patient with both VKORC.-1639 A/A and CYP2C9*1/*3 genotypes

Abstract

The initiation phase of vitamin K antagonist (VKA) is a challenging and demanding process that can result in adverse event such as bleeding. Dosing is influenced by a variety of acquired factors, while another factor that is associated with the optimal dose is the presence of certain genetic variants. We describe a 73 years old male who required extremely low dose of acenocoumarol (0.33 mg/day) to reach the target INR of 2-2.5. During initiation of VKA he started with usually recommended doses of acenocoumarol: 4 mg/day for the first 2 days and 3 mg/day during next 2 days. On fifth day of initiation, massive haematuria occurred and INR level of 10.5 was recorded. Patient was transfused with three doses of fresh frozen plasma in order to stop the bleeding. Acenocoumarol dose was gradually reduced after every INR laboratory monitoring and finally a dose of 0.33 mg/day was required for maintain stable anticoagulation. The genotyping results performed after introducing of VKA showed the patient was homozygous for vitamin K epoxide reductase (VKORC1) c.-1639 G>A, and heterozygous for cytochrome P450 2C9 (CYP2C9)*3 which pointed to extreme sensitivity to acenocoumarol. Our case supports the need for prospective genotyping of CYP2C9 and VKORC1 prior to initiation of VKA where pharmacogenetics, as a good predictor of extreme sensitivity to VKA, could help to tailor optimal VKA dose.

Estimation and Validation of Acenocoumarol Dosing Algorithms In Bulgarian Patients with Cardiovascular Diseases

“…Other studies also demonstrated the influence of age on the dosage of acenocoumarol, but the mechanism of this association has not been fully elucidated yet. [8,[30][31][32][33].…”

Molecular Basis of Thrombophilia / MOLEKULARNE OSNOVE TROMBOFILIJE

“…Poly morphisms in genes CYP2C9 (encoding the main cytochrome P4590 enzyme) and VKORC1 (encoding the warfarin target vitamin K epoxide reductase) were associated with variability in warfarin dose requirement (45)(46)(47)(48). Current knowledge about the genetic factors affecting other anticoagulants is more limited and this area requires future studies (46).…”

Acenocoumarol Pharmacogenetic Dosing Algorithms and Their Application in Two Bulgarian Patients with Low Anticoagulant Requirements

“…The hemorrhages are the most common complications in anticoagulation with coumarin derivates (Esmerian et al 2010;Gage and Lesko 2008;Kovac et al 2011;van der Meer et al 1996) and the risk is higher during the first weeks of the therapy (Hylek et al 2007;Li et al 2006). The prolonged episodes of bleeding have been observed in 12% of treated patients (Levine et al 1998).…”

“…Other important factors are age, diet, height, and weight of patients and potential drug interactions, such as co-administration of amiodarone and other medications. The concurrent carriage of CYP2C9*2/*3, VKORC1 1173T/T, and VKORC1-1639 A/A genotypes in patients with higher risk of thrombosis suggests the lowest dose requirement of acenocoumarol and a significantly increased risk of bleeding complications (Kovac et al 2011).…”